Use of substituted 2-(diaza-bicyclo-alkyl)-pyrimidone derivatives for the treatment of neurodegenerative diseases

ABSTRACT

The invention relates to therapeutic uses of a 2-(diaza-bicyclo-alkyl)-pyrimidone derivative represented by formula (I):  
                 
Wherein R1, R2, R3, R4 and n are as defined herein. Specifically, the compounds of formula (I) are used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer&#39;s disease. The invention relates also to intermediates for the preparation of compound of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/219,923, filed Sep. 6, 2005, now allowed, which is a continuation ofInternational Application No. PCT/EP2004/003050, filed Mar. 5, 2004,which claims the benefit of priority of EP Applications Nos. 03290570.5and 03290571.3, both filed on Mar. 7, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

2. Description of the Art

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitiniilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylatioon. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors.

Moreover, it has been shown that β-amyloid-induced increase in GSK3βactivity results in the phosphorylation and, hence the inhibition ofpyruvate dehydrogenase, a pivotal enzyme in energy production andacetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease, taupathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma.

In addition GSK3β may find application in the treatment of otherdiseases such as: Non-insulin dependent diabetes (such as diabetes typeII ) and obesity; manic depressive illness; schizophrenia; alopecia;cancers such as breast cancer, non-small cell lung carcinoma, thyroidcancer, T or B-cell leukemia and several virus-induced tumors.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax. Recent studies havedemonstrated that β-amyloid increases the GSK3β activity and tau proteinphosphorylation. Moreover, this hyperphosphorylation as well as theneurotoxic effects of β-amyloid are blocked by lithium chloride and by aGSK3β antisense mRNA. These observations strongly suggest that GSK3β maybe the link between the two major pathological processes in Alzheimer'sdisease: abnormal APP (Amyloid Precursor Protein) processing and tauprotein hyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

SUMMARY OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat Gr compounds represented by the following formula (I) had thedesired activity and were useful as an active ingredient of a medicamentfor preventive and/or therapeutic treatment of the aforementioneddiseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus provides novel compounds, including thesalts, solvates or hydrates thereof that are2-(diaza-bicyclo-alkyl)-pyrimidone derivatives represented by formula(I):

wherein:

-   R1 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;-   R2 represents a hydrogen atom, a C₁₋₆ alkyl group optionally    substituted by 1 to 4 substituents selected from a halogen atom, a    hydroxyl group, a C₁₋₄ alkoxy group; a-   C₁₋₂ perhalogenated alkyl group, a benzyl group, a phenethyl group,    a benzyloxycarbonyl group, a C₁₋₄ alkoxy carbonyl group, a benzene    ring, a naphthalene ring, a quinoline ring, a phthalazine ring, a    5,6,7,8-tetrahydronaphthalene ring, a pyridine ring, an indole ring,    a pyrrole ring, a thiophene ring, a benzenesulfonyl group, a benzoyl    group, a pyridazine ring, a furan ring and an imidazole ring; each    of the benzyl group, the phenethyl group, the benzyloxycarbonyl    group, the benzenesulfonyl group, the benzoyl group and the benzene,    naphthalene, quinoline, phthalazine, 5,6,7,8-tetrehydronaphthalene,    pyridine, indole, pyrrole and thiophene rings being optionally    substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group,    a benzene ring, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a    C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group,    a nitro group, a cyano group, an amino group, a C₁₋₆ monoalkylamino    group and a C₂₋₁₀ dialkylamino group;-   R3 represents a 2, 4 or 5-pyrimidine ring or a 2, 3 or 4-pyridine    ring, the rings being optionally substituted by a C₁₋₄ alkyl group,    C₁₋₄ alkoxy group or a halogen atom;-   R4 represents a C₁₋₄ alkyl group optionally substituted by a    hydroxyl group, a C₁₋₄ alkoxy group or a halogen atom; and n    represents 1 or 2; or a salt thereof, or a solvate thereof or a    hydrate thereof.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II ) and obesity;manic depressive illness; schizophrenia; alopecia; cancers such asbreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;

cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the 2-(diaza-bicyclo-alkyl)-pyrimidone derivatives offormula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of the 2-(diaza-bicyclo-alkyl)-pyrimidone derivatives offormula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof; and a use of a substanceselected from the group consisting of the2-(diaza-bicyclo-alkyl)-pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen have been substituted by a halogen, for example a CF₃or C₂F_(5;)

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by an halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

The leaving group represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-l-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,hydroxylysine, and arginine. The base-addition salts of acidic compoundsare prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the 2-(diaza-bicyclo-alkyl)-pyrimidone derivativesrepresented by the aforementioned formula (I) and salts thereof, theirsolvates and hydrates also fall within the scope of the presentinvention. The 2-(diaza-bicyclo-alkyl)-pyrimidone derivativesrepresented by the aforementioned formula (I) may have one or moreasymmetric carbon atoms. As for the stereochemistry of such asymmetriccarbon atoms, they may independently be in either (R) and (S)configuration, and the derivative may exist as stereoisomers such asoptical isomers, or diastereoisomers. Any stereoisomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds.

One of the embodiments of the present invention represented by formula(I) include also: Compounds wherein R3 represents a 4- or 5-pyrimidinering and more preferably 4-pyrimidine ring or R3 represents a 3- or4-pyridine ring and more preferably a 4-pyridine ring, the rings beingoptionally substituted by a C₁₋₂ alkyl group, a C₁₋₂ alkoxy group or ahalogen atom.

Another embodiment of the present invention include compoundsrepresented by formula (I) as follows:

-   (1) Compounds wherein R1 represents a hydrogen atom, a C₁₋₃ alkyl    group or a halogen atom; more preferably a hydrogen atom; and/or-   (2) Compounds wherein when R3 represents a pyrimidine ring    optionally substituted, R2 represents a hydrogen atom, a benzyl    group, a phenethyl group, a benzyloxycarbonyl group, a C₁₋₄ alkoxy    carbonyl group, a benzene ring, a quinoline ring, a phthalazine    ring, a pyridine ring, a benzenesulfonyl group, a benzoyl group or a    pyridazine ring; the benzyl group, the phenethyl group, the    benzyloxycarbonyl group, the benzenesulfonyl group, the benzoyl    group and the rings being optionally substituted by 1 to 4    substituents; or when R3 represents a pyridine ring optionally    substituted, R2 represents a hydrogen atom, a C₁₋₄ alkoxy carbonyl    group, a pyridine ring, a benzene ring, a naphthalene ring, a benzyl    group, a benzoyl group; the groups or the rings being optionally    substituted; and/or-   (3) Compounds wherein R3 represents an unsubstituted 4-pyrimidine    ring; and/or-   (4) R4 represents a C₁₋₂ alkyl group preferably a methyl.

Particularly compounds of the present invention represented by formula(I), wherein R3 is a pyrimidine ring, include compounds:

-   1:    (1S)-1-Methyl-2-[5-(5-phenyl-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl    ]-1H-[4,4′]bipyrimidinyl-6-one,-   2:    (1S)-1-Methyl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,-   3:    (1S)-1-Methyl-2-(5-quinolin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,-   4:    (1R)-1-Methyl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H    -[4,4′]bipyrimidinyl-6-one,-   5:    (1S)-2-[5-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   6:    (1R)-2-[5-(6-Chloro-quinolin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   7:    (1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic    acid tert-butyl ester,-   8:    (1S)-2-[5-(6-Bromo-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   9:    (1S)-2-[5-(6-Chloro-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   10:    (1S)-2-[5-(5-Bromo-pyridin-2-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   11:    (1S)-2-[5-(4-Chloro-phthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   12:    (1S)-2-[5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   13:    (1S)-2-[5-(3-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   14:    (1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   15:    (1S)-1-Methyl-2-(5-p-tolyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,-   16:    (1S)-2-(5-Benzoyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   17:    (1S)-1-Methyl-2-[5-(toluene-4-sulfonyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1H-[4,4′]bipyrimidinyl-6-one,-   18:    (1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic    acid benzyl ester-   19:    (1S)-1-Methyl-2-(5-phenethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,-   20:    (1S)-2-(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   21:    (1S)-2-[5-(2(S)-Hydroxy-2-phenyl-ethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   22    (1S)-1-Methyl-2-(5-pyridin-2-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,-   23:    (1S)-1-Methyl-2-(5-pyridin-4-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]    bipyrimidinyl-6-one,-   24:    (1S)-2-(5-(4-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   25:    (1S)-2-(5-(4-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   26:    (1S)-2-(5-(4-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   27:    (1S)-2-(5-(4-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   28:    (1S)-2-(5-(4-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   29:    (1S)-2-(5-(4-Phenyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   30:    (1S)-2-(5-(4-Trifluoromethyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   31:    (1S)-2-(5-(3-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   32:    (1S)-2-(5-(3-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   33:    (1S)-2-(5-(3-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   34:    (1S)-2-(5-(3-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   35:    (1S)-2-(5-(3-Cyano-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,-   36:    (1S)-2-(5-(3-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;    and compounds of the present invention represented by formula (I)    wherein R3 is a pyridine ring:-   1′:    (1S)-5-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic    acid tert-butyl ester-   2′:    (1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   3′:    (1S)-2-[5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   4′:    (1S)-3-Methyl-6-pyridin-4-yl-2-(5-p-tolyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3H-pyrimidin-4-one,-   5′:    (1S)-2-[5-(4-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6pyridin-4-yl-3H-pyrimi    din-4-one,-   6′:    (1S)-2-[5-(4-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   7′:    (1S)-2-(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   8′:    (1S)-2-[5-(4-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   9′:    (1S)-2-[5-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   10′:    (1S)-2-[5-(4-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   11′:    (1S)-2-[5-(3-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   12′: (1S)-3-Methyl-6-pyridin-4-yl-2-(5-pyridin-    -yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3H-pyrimidin-4-one,-   13′:    (1S)-2-[5-(3-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-metli-pyridin-4-yl-3H-pyrimidin-4-one,-   14′:    (1S)-2-[5-(3-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   15′:    (1S)-2-[5-(4-Ethoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,-   16′: (    1S)-2-[5-(4-Trifluoromethyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one-   17′:    (1S)-2-[5-(4-Phenyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,    and-   18′:    (1S)-2-[5-(3-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

As a further object, the present invention concerns also methods forpreparing the 2-(diaza-bicyclo-alkyl)-pyrimidone compounds representedby the aforementioned formula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

2-(Diaza-bicyclo-alkyl)-pyrimidone compounds represented by theaforementioned formula (I), wherein R2 is as defined previously but nota hydrogen, may be prepared according to the method described in thescheme 1.

(In the above scheme the definition of R1, R3, R4 and n are the same asthose already described for compound of formula (I)).

Following this method, the pyrimidinone derivative represented by theabove formula (II), wherein R1, R3, R4 and n are as defined for compoundof formula (I), is allowed to react, according to well known method inthe art, with a compound of formula (III), wherein R2 is as defined forcompound of formula (I) but not a hydrogen. For example the reaction maybe carried out in a presence of a base such as alkoxide, amine orcarbonate bases such as sodium tert-butoxide, triethylamine or cesiumcarbonate, in a solvent such as tetrahydrofuran or dimethylformamide andthe like to give compound of formula (I).

More particularly, when R2 is an aryl group or a heteroaryl group suchas defined for compound of formula (I), the reaction may be carried outaccording to Buchwald et al's method by a palladium-catalyzed amination(J. Org. Chem. 1997, 62, 6066-6068; J. Ami. Chem. Soc. 1996, 118,7217-7218). That is, the reaction is carried out in a presence ofalkoxide, amine or carbonate bases, for example sodium tert-butoxide,triethylamine or cesium carbonate, and a palladium catalyst such as forexample palladium(II) acetate with a ligand such as

-   (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in a solvent    such as tetrahydrofuran, dimethylformamide, tetraglyme or    polyethylene glycol, at a suitable temperature ranging from 25° to    130 ° C. under inert atmosphere.

Alternatively, 2-(diaza-bicyclo-alkyl)-pyrimidone compounds representedby the aforementioned formula (I), wherein R2 is as defined previouslyfor compound of formula (I), may be prepared according to scheme 2.

(In the above scheme the definition of R1, R2, R3, R4 and n are the sameas already described for compound of formula (I)).

Following this method, compound of formula (XI), wherein R1, R3 and R4are as defined for compound of formula (I) and L represents a leavinggroup such as for example a chlorine or bromine atom, is allowed toreact with a compound of formula (X) wherein n and R2 are as defined forcompound of formula (I). The reaction may be carried out in a presenceof a base such as for example sodium hydride or triethylamine in asolvent such as dimethylformamide or tetrahydrofuran at a temperatureranging from 20° to 60° C.

The compound of formula (II) may be prepared according to the methoddefined in scheme 3.

(In the above scheme the definition of R1, R3, R4 and n are the same asalready described for compound of formula (I)).

According to this method, the 3-ketoester of formula (IV), wherein R1and R3 are as defined for compound formula (I) and R is an alkyl groupsuch as for example a methyl or ethyl group, is allowed to react withN-alkylthiourea of formula (V) wherein R4 is as defined for compound offormula (I). The reaction may be carried out in the presence of a basesuch as 1,8-diazabicyclo[5.4.0]undec-7-ene, in a alcoholic solvent suchas ethanol, at a suitable temperature ranging from 25° to 140° C. underordinary air to give the thiopyrimidone derivative of formula (VI). Thethiopyrimidone derivative of formula (VI) is allowed to react withphosphorus oxychloride in a solvent such as dimethylformamide, at asuitable temperature ranging from 0° to 55° C. under argon atmosphere togive the 2-chloropyrimidone derivative of formula (VII). This latter offormula (VII) is then reacted with a compound of formula (VIII), whereinPg is a protecting group such as for example a tert-butoxycarbonylgroup, in the presence of a base such as triethylamine in a solvent suchas tetrahydrofuran, at a suitable temperature ranging from 0° to 25° C.,to give compound of formula (IX). The compound of formula (IX) is thendeprotected according to well known method in the art such as forexample when the protecting group is a tert-butoxycarbonyl group, in thepresence of trifluoroacetic acid in a solvent such as dichloromethane atroom temperature to give the aforementioned formula (II).

Alternatively, compounds of formula (II) wherein R1 represents a halogenatom such as a bromine atom or a chlorine atom, may be obtained byhalogenation of a compound of formula (II) wherein R1 is a hydrogenatom. The reaction may be carried out in an acidic medium such as aceticacid or propionic acid, in presence of bromosuccinimide orchlorosuccinimide, or bromine.

In addition, compounds of formula (II), wherein RI represents a fluorineatom, may be obtained by analogy to the method described in TetrahedronLetters, Vol.30, N^(o) 45, pp 6113-6116, 1989.

Compounds of formula (III), (IV), (V), (VIII), (XI) and (X) arecommercially available or may be synthesized according to well-knownmethods to one skilled in the art.

For example compounds of formula (IV), wherein R3 and R1 are as definedfor compound of formula (I) and R is an alkyl group such as a methyl oran ethyl, can be prepared by reacting a pyrimidine-carboxylic acid orpyridine-carboxylic acid, optionally substituted by a C₁₋₄ alkyl group,C₁₋₄ alkoxy group or an halogen, with the corresponding malonic acidmonoester. The reaction can be carried out using methods well known toone skilled in the art, such as for example in presence of a couplingagent such as 1,1′-carbonylbis-1H-imidazole in a solvent such astetrahydrofuran at a temperature ranging from 20° to 70° C.

For example compounds of formula (VIII) with the absolute configuration(1R) can be prepared according to EP-400661.

As a further object, the present invention concerns also the compound offormula (II) as intermediate for preparing compounds of formula (I).

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β.

Accordingly, the compounds of the present invention are useful as anactive ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (1).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline.

Sustained-release preparations such as those coated with a polymer maybe directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives.

Generally, the pharmaceutical additives may be incorporated in a ratioranging from 1% by weight to 90% by weight based on the weight of anactive ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be0.01to 1,000 mg (the weight of an active ingredient), and the dose maybe administered once a day or several times a day as divided portions,or once in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1

(Compound N^(o) 7 of table 1)

(1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. (Free base) 1.1.2-Mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one

A mixture containing 77.0g (0.4 mol) of ethyl3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the methoddescribed in patent DE 2705582), 107.0 g (1.19 mol) of N-methylthiourea,60.4 g (0.4 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 773 ml ofethanol was heated under reflux during 2 h.

The cooled mixture was treated with 25.8 ml (0.40 mol) ofmethanesulfonic acid diluted in 157.2 ml of water and the precipitaterecovered by filtration to afford 72 g of pure product as a yellowsolid.

Mp: 219-221° C.

1.2 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one

To a solution of 300 ml of dimethylformamide was added 70 ml (0.75 mol)of phosphorus oxychloride at 0° C. and the resulting solution wasstirred at same temperature for 15 min.

There is added 67.1 g (0.305 mol) of2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one and the resultingsolution was stirred at 55° C. for 2 h.

The mixture was poured into ice-water, adjusted to pH 8 with sodiumhydrogen carbonate and extracted with ethyl acetate. The organicextracts were dried over sodium sulfate and evaporated to give 44.6 g(66%) of the desired compound.

Mp: 150-152° C.

1.3(1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester.

A mixture containing 1.95 ml (14 mmol) of triethylamine, 2.45 g (11mmol) of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one, 2.58 g (13mmol) of (1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester in 100 ml of anhydrous tetrahydrofuran was stirred atroom temperature for 2 h. Water was added to the cooled mixture and theresulting solution extracted with ethyl acetate. The combined extractswere washed with saturated aqueous ammonium chloride and evaporated. Thecrude product was purified by chromatography on silica gel eluting witha mixture of dichloromethane/methanol in the proportions 100/0 to 98/2to afford 4.2 g of pure product as a white solid.

Mp: 198-200° C.

¹H NMR (200 MHz; DMSO-d⁶): δ 9.25 (s, 1H); 8.97 (d, 1H); 8.19 (s, 1H);6.81(s, 1H); 4.85 (br s, 1H); 4.42 (br s, 1H); 3.84 (dd, 1H); 3.56-3.74(m, 1H); 3.35-3.54 (m, 2H); 3.35 (s, 3H); 1.88 (br s, 2H); 1.34 (s, 9H).

Example 2

(Compound N^(o) 14 of table 1)

(1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one hydrochloride (1:1)

To a solution of 4.45 g (11.58 mmol) of(1S)-5-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester in 25 ml of anhydrous dichloromethane was added10.71 ml (139 mmol) of trifluoroacetic acid and the resulting mixturewas stirred at room temperature for 2 h.

The mixture was poured into ice-water, adjusted to pH 8 with potassiumcarbonate and extracted with chloroform. The organic extracts were driedover sodium sulfate and evaporated. The product obtained in the form offree base was transformed into the hydrochloride salt to give 4 g (69%)of pure compound as a yellow solid.

Mp 275-277° C. ¹HNMR (200 MHz; DMSO-d⁶) δ 9.28 (s, 1H); 9.15 (br s,1H(NH)); 8.96 (d, 1H); 8.22 (d, 1H); 6.88 (s, 1H); 4.88 (br s, 1H); 4.43(br s, 1H); 3.89 (dd, 1H); 3.69 (br d, 1H); 3.24-3.46 (m, 2H); 3.33 (s,3H); 2.03 (AB, 2H).

Example 3

(Compound N^(o) 2 of table 1)

(1S)-1-Methyl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-onehydrochloride (1:1).

A mixture containing 1.76 g (6.28 mmol) of(1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,2.18 ml (22.67 mmol) of 3-bromopyridine, 3.44 g (10.56 mmol) of cesiumcarbonate, 187 mg (0.3 mmol) of(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 67 mg (0.3 mmol)of palladium(II) acetate in 100 ml of anhydrous tetrahydrofuran underargon atmosphere was stirred under reflux for 18 h. The mixture wasfiltered and water was added to the mixture and the resulting solutionextracted with chloroform. The combined extracts were washed withsaturated aqueous ammonium chloride and evaporated. The crude productwas purified by chromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 95/5. The productobtained in the form of free base was transformed into the hydrochloridesalt to give 650 mg (26%) of pure compound as a solid.

Mp: 180-182° C.

¹HNMR (200 MHz; DMSO-d⁶): δ 9.22 (d, 1H); 8.98 (d, 1H); 8.22 (dd, 1H);8.13 (br s, 1H); 7.98 (t, 1H); 7.63-7.78 (m, 2H); 6.77 (s, 1H); 5.02 (s,1H); 4.87 (s, 1H) 3.90 (d, 1H); 3.72 (s, 2H); 3.58 (d, 1H); 3.31(s, 3H);2.10 (AB, 2H).

Example 4

(Compound N^(o) 16 of table 1)

(1S)-2-(5-Benzoyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one

To a solution of 0.13 g (0.46 mmol) of(1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-onein 3 ml of anhydrous dimethylformamide was added 24 mg (0.6 mmol) ofsodium hydride and the resulting mixture was stirred at 0° C. for 15min. There is added 0.07 ml (0.6 mmol) of benzoyl chloride and theresulting solution was stirred at 0° C. for 2h. Water was added to themixture and the resulting solution extracted with ethyl acetate. Thecombined extracts were washed with saturated aqueous ammonium chlorideand evaporated. The crude product was purified by chromatography onsilica gel eluting with a mixture of dichloromethane/methanol in theproportions 100/0 to 97/3 to give 90 mg (50%) of pure compound as asolid.

Mp: 133-135° C.

¹HNMR (400 MHz; DMSO-d⁶) (Two conformers are present in the NMR spectra.Only the chemical displacements of the major one are given) δ 9.31(s,1H); 9.05 (d, 1H); 8.30 (d, 1H); 7.37-7.60 (m, 5H); 6.89 (s, 1H); 4.96(s, 1H); 4.92 (s, 1H); 3.72-3.94 (m, 2H); 3.39 (s, 3H); 3.22-3.35 (m,2H); 1.91-2.12 (m, 2H).

Example 5

(Compound N^(o) 1′ of table 2)

(1S)-5-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. (Free base) 5.1 2-Mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

A mixture containing 70.0 g (0.36 mol) of ethyl3-(4-pyridinyl)-3-oxopropionate, 98.1 g (1.09 mol) of N-methylthiourea,55.0 g (0.36 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 551 ml ofethanol is heated under reflux during 2 h. The cooled mixture is treatedwith 34.9 ml (0.36 mol) of methanesulfonic acid in 143.6 ml of water andthe precipitate recovered by filtration to afford 60.4 g of pure productas a white solid.

Mp: 250-252° C.

5.2 2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride(1:1)

To a solution of 180 ml of dimethylformamide is added 16 ml (0.17 mol)of phosphorus oxychloride at 0° C. and the resulting solution is stirredat same temperature for 20 min. There is added 24.15 g (0.11 mol) of2-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one and the resultingsolution is stirred at 70° C. for 5 h. The mixture is poured intoice-water and the precipitate recovered by filtration to afford 28 g ofpure product as a white solid.

Mp: 261-263° C.

5.3(1S)-5-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. (Free base)

A mixture containing 10.7 ml (78.14 mmol) of triethylamine, 13.6 g (52.7mmol) of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-onehydrochloride (1:1), 6.0 g (30.24 mmol) of(1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterin 500 ml of anhydrous dimethylformamide is stirred at 20° C. for 6 h.Water is added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts are washed withsaturated aqueous ammonium chloride and saturated aqueous sodiumchloride then evaporated. The crude product is refluxed in diethyl etherfor 1 h to afford 8.36 g of pure product as a brown solid.

Mp: 174-176° C.

¹HNMR (200 MHz ; CDCl₃): δ 8.73 (d, 2H); 7.78 (d, 2H); 6.58 (s, 1H);4.83 (br s, 1H); 4.62 (br d, 1H); 3.69-4.02 (m, 1H); 3.77 (dd, 1H);3.34-3.64 (m, 2H); 3.49 (s, 3H); 2.00 (br s, 2H); 1.49 (s, 9H).

Example 6

(Compound N^(o) 2′ of table 2)

(1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-onehydrochloride (1:2)

To a solution of 8.36 g (21.8 mmol) of(1S)-5-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester in 50 ml of anhydrous dichloromethane is added 20ml (261.6 mmol) of trifluoroacetic acid and the resulting mixture isstirred at room temperature for 2h. The mixture is poured intoice-water, adjusted to pH 8 with potassium carbonate and extracted withchloroform. The organic extracts were dried over sodium sulfate andevaporated. The crude product is triturated with ethyl acetate to afford5 g of pure product as a brown solid which was transformed into thedihydrochloride salt.

Mp: 240-242° C.

¹HNMR (200 MHz; DMSO-d⁶): δ 9.18 (br s, 1H (NH)); 8.88 (d, 2H); 8.38 (d,2H); 6.90 (s, 1H); 4.89 (br s, 1H); 4.43 (br s, 1H); 3.84 (AB, 2H);3.55-3.78 (m, 2H); 3.38 (s, 3H); 2.03 (AB, 2H).

Example 7

(Compound N^(o) 12′ of table 2)

(1S)-3-Methyl-6-pyridin-4-yl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3H-pyrimidin-4-one

A mixture containing 0.2 g (0.71 mmol) of(1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,3.335 g (2.12 mmol) of 3-bromopyridine, 0.322 g (0.99 mmol) of cesiumcarbonate, 18 mg (0.028 mmol) of(+/−)-2,2′-bis(diphenylplhosphino)-1,1′-binaphthyl and 6 mg (0.028 mmol)of palladium(II) acetate in 100 ml of anhydrous tetrahydrofuran underargon atmosphere is stirred under reflux for 18 h. The mixture isfiltered. Water is added to the filtrate and the resulting solutionextracted with chloroform. The combined extracts are washed withsaturated aqueous ammonium chloride and evaporated. The crude product ispurified by chromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 95/5 to give 119 mgof pure compound as a solid.

Mp : 179-181° C.

¹HNMR (200 MHz ; DMSO-d⁶): δ 9.65 (d, 2H); 7.98 (s, 1H); 7.91(d, 2H);7.79 (d, 1H); 6.90-7.15 (m, 2.H); 6.55 (s, 1H); 4.92 (br s, 1H); 4.69(br s, 1H); 3.85 (dd, 1H); 3.67 (dd, 1H); 3.42-3.60 (m, 2H); 3.28 (s,3H); 2.05 (br s, 2H).

Example 8

(Compound N^(o) 10′ of table 2)

(1S)-2-[5-(4-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

To a solution of 0.10 g (0.35 mmol) of(1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-onein 3 ml of anhydrous tetrahydrofuran is added 0.06 ml (0.46 mmol) ofanhydrous triethylamine and the resulting mixture is stirred at roomtemperature for 20 min.

To the cooled mixture is added 0.064 ml (0.46 mmol) of 4-methyl-benzoylchloride and the resulting solution allowed to stir at room temperaturefor 2 h. Water is added to the mixture and the resulting solutionextracted with dichloromethane. The combined extracts are washed withsaturated aqueous ammonium chloride and evaporated. The crude product ispurified by chromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 97/3 to give 106 mg of purecompound as a solid.

Mp: 118-120° C.

¹HNMR (200 MHz; CDCl₃) δ 8.72 (br s, 2H); 7.75 (br d, 2H); 7.45 (br s,2H); 7.15-7.35 (m, 2H); 6.58 (br s, 1H); 4.90 (AB, 2H); 3.65-4.26 (m,4H); 3.50 (s, 3H); 2.41(br s, 3H); 2.09 (br d, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I) illustrating the present invention is givenin table 1. The compounds have been prepared according to the methods ofthe example.

In the table 1and 2, (S) or (R) indicate the stereochemistry of thecarbon atom, Ph represents a phenyl group.

In table 1 R3 is an unsubstituted 4-pyrimidine ring and R4 is a methylgroup.

In table 2 R3 is an unsubstituted 4-pyridine ring and R4 is a methylgroup. TABLE 1 (I)

Absolute N^(o) configuration * R1 R2 n Mp ° C. salt 1 (1S) H

1 52 (1:1) (hydrochloride) 2 (1S) H

1 180-182 (1:1) (hydrochloride) 3 (1S) H

1 183-184 (1:1) (hydrochloride) 4 (1R) H

1 178-180 (1:1) (hydrochloride) 5 (1S) H

1 202-204 Free base 6 (1S) H

1 232-234 Free base 7 (1S) H

1 198-200 Free base 8 (1S) H

1 245-247 Free base 9 (1S) H

1 265-267 Free base 10 (1S) H

1 241-243 Free base 11 (1S) H

1 217-219 Free base 12 (1S) H

1 237-239 Free base 13 (1S) H

1 203-205 Free base 14 (1S) H H 1 275-277 (1:1) hydrochloride 15 (1S) H

1 225-227 Free base 16 (1S) H

1 133-135 Free base 17 (1S) H

1 212-214 Free base 18 (1S) H

1 100-102 Free base 19 (1S) H

1 110-112 Free base 20 (1S) H

1 155-157 Free base 21 (1S) H

1 187-189 Free base 22 (1S) H

1 280-282 (1:1) hydrochloride 23 (1S) H

1 252-254 (1:1) hydrochloride 24 (1S) H

1 142-144 Free base 25 (1S) H

1 152-154 Free base 26 (1S) H

1 191-193 Free base 27 (1S) H

1 131-133 Free base 28 (1S) H

1 144-147 Free base 29 (1S) H

1 135-137 Free base 30 (1S) H

1 207-209 Free base 31 (1S) H

1 181-183 Free base 32 (1S) H

1 185-187 Free base 33 (1S) H

1 178-180 Free base 34 (1S) H

1 199-201 Free base 35 (1S) H

1 228-230 Free base 36 (1S) H

1 192-194 Free base

TABLE 2 (I)

Absolute N^(o) configuration R1 R2 n Mp ° C. salt  1′ 1 (S) H

1 174-176 Free base  2′ 1-(S) H H 1 240-242 (1:2) (hydrochloride)  3′1-(S) H

1 251-253 Free base  4′ 1-(S) H

1 123-125 Free base  5′ 1-(S) H

1 115-117 (1:1) (hydrochloride)  6′ 1-(S) H

1 116-118 (1:1) (hydrochloride)  7′ 1-(S) H

1 162-164 Free base  8′ 1-(S) H

1 118-120 Free base  9′ 1-(S) H

1 185-187 Free base 10′ 1-(S) H

1 118-120 Free base 11′ 1-(S) H

1 184-186 (1:1) (hydrobromide) 12′ 1-(S) H

1 179-181 Free base 13′ 1-(S) H

1 165-167 Free base 14′ 1-(S) H

1 150-152 Free base 15′ 1-(S) H

1 110-112 Free base 16′ 1-(S) H

1 193-195 Free base 17′ 1-(S) H

1 232-234 Free base 18′ 1-(S) H

1 155-157 Free base

Test Example

Inhibitory Activity of the Medicament of the Present Invention againstGSK3β:

Two different protocols can be used.

In a first protocol : 7.5 μM of prephosphorylated GS1peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume : 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilized in DMSO (final solventconcentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1is between 1nanomolar to 1 micromolarconcentrations.

For example compound No. 24 of table 1 shows an IC₅₀ of 0.006 μM andcompound No. 4′ of table 2 shows an IC₅₀ of 0.004 μM.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus. Compound of Example 1 30 mg Crystallinecellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules. Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule. Compound of Example 1 3 mgSodium chloride 4 mg Distilled water for injection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A method for the treatment of a disease selected from the groupconsisting of Alzheimer's disease, Parkinson's disease, taupathies,non-insulin dependent diabetes, obesity, manic depressive illness andschizophrenia, which comprises administering to a patient in need ofsaid treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein: n represents 1 or 2; R1 represents a hydrogen atom, a C₁₋₆alkyl group or a halogen atom; R2 represents a hydrogen atom, a C₁₋₆alkyl group optionally substituted by 1 to 4 substituents selected froma halogen atom, a hydroxyl group, a C₁₋₄ alkoxy group; a C₁₋₂perhalogenated alkyl group, a benzyl group, a phenethyl group, abenzyloxycarbonyl group, a C₁₋₄ alkoxy carbonyl group, a benzene ring, anaphthalene ring, a quinoline ring, a phthalazine ring, a5,6,7,8-tetrahydronaphthalene ring, a pyridine ring, an indole ring, apyrrole ring, a thiophene ring, a benzenesulfonyl group, a benzoylgroup, a pyridazine ring, a furan ring and an imidazole ring; each ofthe benzyl group, the phenethyl group, the benzyloxycarbonyl group, thebenzenesulfonyl group, the benzoyl group and the benzene, naphthalene,quinoline, phthalazine, 5,6,7,8-tetrehydronaphthalene, pyridine, indole,pyrrole and thiophene rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a benzene ring, a halogenatom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,a hydroxyl group, a C₁₋₄ alkoxy group, a nitro group, a cyano group, anamino group, a C₁₋₆ monoalkylamino group and a C₂₋₁₀ dialkylamino group;R3 represents a 2, 4 or 5-pyrimidine ring or a 2, 3 or 4-pyridine ring,the rings being optionally substituted by a C₁₋₄ alkyl group, C₁₋₄alkoxy group or a halogen atom; and R4 represents a C₁₋₄ alkyl groupoptionally substituted by a hydroxyl group, a C₁₋₄ alkoxy group or ahalogen atom.
 2. The method according to claim 1, wherein R3 representsan unsubstituted 4-pyrimidine ring or an unsubstituted 4-pyridine ring.3. The method according to claim 1, wherein, when R3 represents anoptionally substituted pyrimidine ring, R2 represents a hydrogen atom;or an optionally substituted, by 1 to 4 substituents, benzyl group,phenethyl group, benzyloxycarbonyl group, C₁₋₄ alkoxy carbonyl group,benzene ring, quinoline ring, phthalazine ring, pyridine ring,benzenesulfonyl group, benzoyl group or pyridazine ring; provided that,when R3 represents an optionally substituted pyridine ring, R2represents an optionally substituted pyridine ring, benzene ring,naphthalene ring, benzyl group, or benzoyl group.
 4. The methodaccording to claim 1, wherein said compound of formula (I) is selectedfrom the group consisting of:(1S)-1-Methyl-2-[5-(5-phenyl-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1H-[4,4′]bipyrimidinyl-6-one,(1S)-1-Methyl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1S)-1-Methyl-2-(5-quinolin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1R)-1-Methyl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(4-Fluoro-plhenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1R)-2-[5-(6-Chloro-quinolin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester(1S)-2-[5-(6-Bromo-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(6-Chloro-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl1-H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(5-Bromo-pyridin-2-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(4-Chloro-phthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-[5-(3-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidiny1-6-one,(1S)-1-Methyl-2-(5-p-tolyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-Benzoyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-1-Methyl-2-[5-(toluene-4-sulfonyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1H-[4,4′]bipyrimidinyl-6-one,(1S)-5-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid benzyl ester(1S)-1-Methyl-2-(5-phenethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidiniyl-6-one,(1S)-2-(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4]bipyrimidinyl-6-one,(1S)-2-[5-(2(S)-Hydroxy-2-phenyl-ethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-1-Methyl-2-(5-pyridin-2-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1S)-1-Methyl-2-(5-pyridin-4-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Phenyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(4-Trifluoromethyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Cyano-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-2-(5-(3-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one,(1S)-5-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester(1S)-2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-3-Methyl-6-pyridin-4-yl-2-(5-p-tolyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3H-pyrimidin-4-one,(1S)-2-[5-(4-Bromo-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Chloro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(3-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-3-Methyl-6-pyridin-4-yl-2-(5-pyridin-3-yl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3H-pyrimidin-4-one,(1S)-2-[5-(3-Methoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]3-methyl-1-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(3-Methyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Ethoxy-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,(1S)-2-[5-(4-Trifluoromethyl-benzoyl)-2,5-diaza-bicyclo[2.2]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one(1S)-2-[5-(4-Phenyl-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,and1S)-2-[5-(3-Fluoro-benzoyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the disease is selected from the group consisting of Alzheimer'sdisease, Parkinson's disease and taupathies.
 6. The method of claim 1,wherein the disease is Alzheimer's disease.
 7. The method of claim 1,wherein the disease is Parkinson's disease.
 8. The method of claim 1,wherein the disease is taupathies.
 9. The method of claim 1, wherein thedisease is selected from the group consisting of non-insulin dependentdiabetes, obesity, manic depressive illness and schizophrenia.
 10. Themethod of claim 1, wherein the disease is non-insulin dependentdiabetes.
 11. The method of claim 1, wherein the disease is obesity. 12.The method of claim 1, wherein the disease is manic depressive illness.13. The method of claim 1, wherein the disease is schizophrenia.